Research reveals how ketamine acts as 'switch' in brain

PENNSYLVANIA: According to a new study by Penn Medicine researchers, ketamine, an established anaesthetic and increasingly popular antidepressant, dramatically reorganises activity in the brain, as if a switch was flipped on its active circuits.

The team described starkly altered neuronal activity patterns in the cerebral cortex of animal models after ketamine administration in a paper published this month in Nature Neuroscience, observing typically active neurons that were silenced and another set that was normally quiet suddenly springing to action.

This ketamine-induced activity switch in key brain regions associated with depression may have implications for our understanding of ketamine's treatment effects and future neuropsychiatric research.

"Our surprising results reveal two distinct populations of cortical neurons, one engaged in normal awake brain function, the other linked to the ketamine-induced brain state," said the co-lead and co-senior author Joseph Cichon, MD, PhD, an assistant professor of Anesthesiology and Critical Care and Neuroscience in the Perelman School of Medicine at the University of Pennsylvania.

"It's possible that this new network induced by ketamine enables dreams, hypnosis, or some unconscious state. And if that is determined to be true, this could also signal that it is the place where ketamine's therapeutic effects take place".

Anesthesiologists routinely administer anaesthetic drugs prior to surgeries to reversibly alter brain activity and induce unconsciousness. Ketamine has been a mainstay in anaesthesia practice since its synthesis in the 1960s due to its consistent physiological effects and safety profile. One of ketamine's distinguishing features is that it maintains some activity states across the brain's surface (the cortex).

In contrast, most anaesthetics work by completely suppressing brain activity. These preserved neuronal activities are thought to be important for ketamine's antidepressant effects in depression-related brain areas. However, the mechanism by which ketamine exerts these clinical effects is still unknown.

In their new study, the researchers analyzed mouse behaviours before and after they were administered ketamine, comparing them to control mice who received placebo saline.

One key observation was that that given ketamine, within minutes of injection, exhibited behavioural changes consistent with what is seen in humans on the drug, including reduced mobility, and impaired responses to sensory stimuli, which are collectively termed "dissociation."

"We were hoping to pinpoint exactly what parts of the brain circuit ketamine affects when it's administered so that we might open the door to better study of it and, down the road, more beneficial therapeutic use of it," said co-lead and co-senior author Alex Proekt, MD, PhD, an associate professor of Anesthesiology and Critical Care at Penn.

Cortical brain tissue was imaged using two-photon microscopy before and after ketamine treatment. They discovered that ketamine activated previously silent neurons while turning off previously active neurons by tracking individual neurons and their activity.

The observed neuronal activity was attributed to ketamine's ability to inhibit the activity of synaptic receptors called NMDA receptors and ion channels called HCN channels.

The researchers discovered that by simply inhibiting these specific receptors and channels in the cortex, they could recreate the effects of ketamine without the medications. Ketamine weakens several sets of inhibitory cortical neurons, which normally suppress other neurons, according to the researchers.

This allowed normally quiet neurons, which are normally suppressed when ketamine is not present, to become active. The study found that this drop in inhibition was required for the activity switch in excitatory neurons, which form communication highways and are the main target of commonly prescribed antidepressants.

More research is needed to determine whether ketamine-driven effects in excitatory and inhibitory neurons are responsible for ketamine's rapid antidepressant effects.

"While our study directly pertains to basic neuroscience, it does point at the greater potential of ketamine as a quick-acting antidepressant, among other applications," said co-author Max Kelz, MD, PhD, a distinguished professor of Anesthesiology and vice chair of research in Anesthesiology and Critical Care.

"Further research is needed to fully explore this, but the neuronal switch we found also underlies dissociated, hallucinatory states caused by some psychiatric illnesses."